Wang, Benjamin W.E.

Abstract Background Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods From November 1, 2019, to June 13, 2025, patients ( n =2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and ≥5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score ≥5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score ( p <0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores ( n =50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p =0.0004, HSD p =0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

Abstract Background: Although hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are inherited disorders expected to display a 1:1 sex ratio, most studies report a strong female dominance. This study analyzed sex differences in 122 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD using the 2017 criteria. Methods: Self-reported data was obtained from November 1, 2019, to April 25, 2025, ( n =2,451) from an Intake Questionnaire of adult (≤18 years old) patients diagnosed with hEDS or HSD at the EDS Clinic at Mayo Clinic Florida and analyzed by sex. Results: We found that 90.6% ( n =575) of hEDS patients were female and 9.4% ( n =60) were male, with a sex ratio of 9.6:1 female-to-male, while 95.2% ( n =1,728) of HSD patients were female and 4.8% ( n =88) were male, with a sex ratio of 19.6:1 female-to-male. Females were older than males: hEDS 35 vs. 28 years of age ( p <0.001), HSD 34 vs. 31 years of age ( p =0.004). Overall, females self-reported more symptoms/comorbidities than males: hEDS 31/122 (25.4%), HSD 59/122 (48.4%). In contrast, only 5/122 (4.1%) symptoms/comorbidities were self-reported more often in males including attention deficit disorder/attention deficit hyperactivity disorder, delay in developmental milestones, snoring, autism spectrum disorder, and obstructive sleep apnea. Females with HSD had more mast cell-related symptoms (i.e., hives p <0.001) which were reflected in higher mast cell scores than males ( p <0.001). Patients with higher mast cell scores also had higher serum levels of total IgE ( p =0.029). More females with HSD were diagnosed with fibromyalgia ( p <0.001) and reported symptoms associated with autonomic dysfunction than males. Aside from abuse, which was higher in females (hEDS p =0.039, HSD p <0.001), few sex differences were reported for psychological symptoms/comorbidities. In support for the idea that elevated mast cell activity in females may lead to extracellular matrix remodeling that promotes hypermobility, females with hEDS/HSD had greater serum collagen-4α1 ( p <0.0001) and fibronectin ( p =0.015) than males by ELISA. Conclusions: Females with hEDS and HSD report a higher burden of symptoms/comorbidities than males, providing a possible explanation for fewer males being reported in demographic data. Sex differences in symptoms/comorbidities may reflect sex differences in pathogenic drivers of disease.